biostudies-literatureCoffey DGNCI NIH HHS220-233https://www.ebi.ac.uk/biostudies/studies/S-EPMC11738034biostudies-literatureUnknown145(2)<h4>Abstract</h4>Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by γ-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the γ-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which BloodSingle-cell analysis of the multiple myeloma microenvironment after γ-secretase inhibition and CAR T-cell therapy.PMC11738034P01 CA018029Atilla EComstock MLGreen DJPont MJRiddell SRLandgren OHill GRAtaca Atilla PCowan AJCoffey DGSimon SfalseSingle-cell analysis of the multiple myeloma microenvironment after γ-secretase inhibition and CAR T-cell therapy.<h4>Abstract</h4>Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by γ-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the γ-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which 2025-01-01T00:00:00Z2025 Jan2026-06-01T17:54:33.355Z2026-04-08T14:25:11.471ZS-EPMC117380343937452210.1182/blood.2024025231